The emergence of bacterial strains that are resistant to conventional antibiotics has prompted a search for new therapeutic agents, including antimicrobial peptides of animal origin. Antimicrobial peptides have been recognized as playing an important role in the innate host defense mechanisms of most living organisms including those of plants, insects, amphibians and mammals, and are known to possess potent antibiotic activity against bacteria, fungi, and certain viruses. The antimicrobial peptides readily partition into phospholipid bilayers with greater than 95% of the peptides binding to lipid to compromise membrane integrity. In bacteria, antimicrobial peptides are able to cause small, transient increases in conductance in planar lipid bilayers, thereby partially depolarizing the cytoplasmic membrane potential gradient.
The protective function of antimicrobial peptides in innate host defense mechanisms has been demonstrated in Drosophila, where reduced expression of such peptides dramatically decreases survival rates after microbial challenge. In mammals, a similar function is suggested by defective bacterial killing in the lungs of cystic fibrosis patients and in small mice.
The antimicrobial peptides found in mammals may be classified into the cysteine-rich defensins (α- and β-defensin) and various groups within the cathelicidin family. Based on the amino acid composition and structure, the cathelicidin family may be classified into three groups. The first group includes the amphipathic α-helical peptides such as LL-37, CRAMP, SMAP-29, PMAP-37, BMAP-27, and BMAP-28. The second group contains the Arg/Pro-rich or Trp-rich peptides including Bac5, Bac7, PR-39, and indolicidin. The third group includes Cys-containing peptides such as protegrins. Cathelicidin families contain a highly-conserved signal sequence and proregion known as the cathelin domain and a variable antimicrobial sequence in the C-terminal domain. Many cathelicidins contain a characteristic elastase cleavage site between the anionic cathelin domain and the cationic C-terminal peptide domain. Proteolytic processing at this site has been observed in bovine and porcine neutrophils and is required for microbicidal activity. Although these antimicrobial peptides have a broad spectrum of activity against many microbial organisms, they may have different hemolytic activities for erythrocytes, so that their pharmaceutical potential is restricted. Therefore, the low hemolytic antimicrobial peptides are disclosed in the present invention, they have not only the outstanding antimicrobial activities but also have low hemolytic activities as well.
As antimicrobial peptides are low molecular mass molecules of less than 5 kDa possessing broad-spectrum activity and constituting an important part of the host defense against microbial infections, they provide a starting point for designing low molecular mass antibiotic compounds. Furthermore, they are known to have a propensity to fold into amphipathic structures with clusters of hydrophobic and charge regions, a feature contributing to their membranolytic activity. Despite these antimicrobial peptides having a broad spectrum of activity against many microbial organisms, they may have different hemolytic activities for erythrocytes, so that their pharmaceutical potential is restricted.